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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, and Department of Radiology, University of Florida College of Medicine, Gainesville, Florida.
Address reprint requests to: Rodney K. Edwards, MD, MS, University of Florida College of Medicine, Department of Obstetrics and Gynecology, PO Box 100294, Gainesville, FL 32610-0294; E-mail: edwardsr{at}obgyn.ufl.edu.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: We performed a randomized clinical trial of ampicillin versus penicillin for intrapartum antibiotic prophylaxis. Genital tract cultures for Enterobacteriaceae were obtained at study entry and 8–36 hours postpartum. Organisms were isolated, identified, and tested for ampicillin susceptibility.
RESULTS: The ampicillin (n = 175) and penicillin (n = 177) groups, respectively, did not differ in rates of ampicillin-resistant Escherichia coli at entry (25% versus 22%, P = .57) or postpartum (36% versus 38%, P = .64). Similarly, groups did not differ in rates of ampicillin-resistant Enterobacteriaceae at entry (38% versus 32%, P = .23) or postpartum (51% versus 55%, P = .46). However, postpartum culture rates of resistant Escherichia coli were higher than entry culture rates for both the ampicillin (36% versus 25%, P = .026) and penicillin (38% versus 22%, P < .001) groups. Postpartum culture rates of resistant Enterobacteriaceae were also higher than entry culture rates for both the ampicillin (51% versus 38%, P < .001) and penicillin (55% versus 32%, P < .001) groups. Results were similar when considering only women who received two or more doses and no additional antibiotics.
CONCLUSION: Intrapartum antibiotic prophylaxis with either ampicillin or penicillin increases exposure of neonates to ampicillin-resistant Enterobacteriaceae.
Administration of intravenous intrapartum antibiotic prophylaxis has been shown to substantially reduce the incidence of early-onset neonatal infection with Streptococcus agalactiae (group B streptococcus).1–3 This fact is the basis for the recommendation by the Centers for Disease Control and Prevention (CDC) that intrapartum antibiotic prophylaxis should be given to women in labor who either have been shown to carry group B streptococci by culture or who develop risk factors for transmission of the organism.4 The American Academy of Pediatrics5 and the ACOG6 also have endorsed the strategy.
The CDC recommended the use of penicillin G preferentially for intrapartum antibiotic prophylaxis because, theoretically, it was less likely to select for antibiotic-resistant organisms because of its narrow spectrum of activity.4 Other authors have agreed with this sentiment, citing penicillin’s favorable pharmacokinetics and its narrower and specific spectrum.7 These recommendations for preferential use of penicillin G over ampicillin were made based solely on expert opinion and not on substantive data. Furthermore, although the CDC recommended penicillin G over ampicillin (which was referred to as an "acceptable alternative"4), most clinical studies evaluating intrapartum antibiotic prophylaxis have employed ampicillin,3,8,9 and, at least in part because of this fact, ampicillin is used extensively for this purpose. In addition to having antimicrobial activity against aerobic streptococci, such as group B streptococci, ampicillin is also bactericidal for many of the aerobic gram-negative bacilli, especially the family Enterobacteriaceae.
The potential for the increased use of antibiotics to lead to more infections caused by resistant organisms has caused concern. Escherichia coli is the second most common cause of early-onset neonatal sepsis, and sepsis caused by ampicillin-resistant E coli results in a greater likelihood of mortality than does sepsis with group B streptococci or ampicillin-sensitive E coli.10,11 Retrospective and observational data from four studies have shown, in association with more widespread use of ampicillin, an increase in the proportion of early-onset neonatal sepsis cases caused by E coli and other Enterobacteriaceae and an increase in the proportion of these pathogens that are resistant to ampicillin12–14 (O’Reilly G, Hitti J, Brock B, Watts DH, Gill P, Benedetti T. Gram-negative sepsis among low-birth-weight infants: Infection rates before and after initiation of group B streptococcus prophylaxis [abstract 0028]. Am J Obstet Gynecol 2001;184:S14).
In contrast to the situation with ampicillin, no data have been published that implicate intrapartum antibiotic prophylaxis with penicillin as increasing the likelihood of early-onset neonatal infection with gram-negative organisms. Unfortunately, neither are there published data that refute such an association. The objective of this study was to assess whether the antibiotic chosen for intrapartum antibiotic prophylaxis affects the exposure of neonates to gram-negative bacteria resistant to ampicillin.
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MATERIALS AND METHODS |
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After women gave written informed consent, and before they received any dose of antibiotics, culture specimens were taken from the lower vagina, perineum, and perianal skin of these subjects. The swabs used to obtain these culture specimens were commercially available dual rayon-tipped swabs with modified Stuart bacterial transport medium (Culturette II, Becton Dickinson, Sparks, MD). One of these swabs was used for the entry specimen for the randomized clinical trial, and the other swab was used for group B streptococcus culture for a concurrent cohort study.
Once the entry swabs had been obtained, subjects were randomized, by selection of the next opaque envelope containing an order sheet, to receive intrapartum antibiotic prophylaxis with ampicillin or penicillin. A random number-generating software program (Research Randomizer, Social Psychology Network, Middleton, CT) was used to assign subjects to groups. The doses of antibiotics administered were consistent with the CDC recommendations.4 Subjects randomized to receive penicillin were given 5 MU of penicillin G intravenously, followed by 2.5 MU every 4 hours until delivered. Those women randomized to receive ampicillin were given 2 g of ampicillin intravenously, followed by 1 g every 4 hours until delivered. Additional antibiotics were administered only if a subject developed chorioamnionitis or required prophylaxis against puerperal endometritis (eg, because of a cesarean delivery or manual placental extraction).
A second culture specimen was obtained from the lower vagina, perineum, and perianal skin of these same subjects 8–36 hours after delivery. For collection of these postpartum specimens, we used a single swab (Culturette, Becton Dickinson, Sparks, MD). Because a single investigator (RKE) collected all postpartum culture specimens, the timing of the postpartum collection was chosen to allow for availability of the investigator and for collection before subjects’ discharge from the hospital.
Within 24 hours of collection, swabs were streaked onto MacConkey agar plates, which were incubated at 37C for 18–24 hours. Isolates were then identified by biochemical reactions using a commercially available prepared multimedia tube (BBL Enterotube II, Becton Dickinson, Sparks, MD). Pure cultures of Enterobacteriaceae isolates were stored in Todd-Hewitt broth plus 15–20% glycerol at -80C until antibiotic susceptibility testing.
Enterobacteriaceae isolates were tested for susceptibility to ampicillin by the agar disk diffusion method described by Bauer et al15 using interpretation zones established by the National Committee for Clinical Laboratory Standards. The E coli American Type Culture Collection 25922 was used as a reference standard.
Subjects’ medical records were reviewed. Demographic data, specific information regarding the course of labor, antibiotic type, and number of doses were entered into a relational database (Access, Microsoft Corp., Redmond, WA). For each isolate, bacterial species, time of culture (study entry or postpartum), and resistance to ampicillin were recorded and entered into the database as well. Dichotomous variables for each patient at study entry and postpartum were generated. These variables indicated ampicillin resistance status for E coli isolates and Enterobacteriaceae species ("absent" for no resistant isolates and "present" for at least one resistant isolate). All data management and analysis were done using SAS 8.0 (SAS Institute, Cary, NC). All tests of statistical significance were two-tailed and used an 
level of 0.05.
Descriptive statistics of demographic, intrapartum, treatment, and outcome factors were generated using means, proportions, and frequency tables, as appropriate. 
2 testing was done to test the null hypotheses that the proportions of subjects with at least one ampicillin-resistant E coli and Enterobacteriaceae isolate in the postpartum culture would be equal between the ampicillin and penicillin groups. In addition, groups were compared for the proportions of ampicillin-resistant isolates in the entry cultures.
Analysis of ampicillin resistance status was done by intent-to-treat (regardless of actual antibiotic dosing), excluding those women who received clindamycin. A per-protocol analysis was also done, including only patients who received at least two doses of the assigned antibiotic and no additional antibiotics before collection of the postpartum culture.
We used the McNemar test to evaluate the null hypotheses that the proportions of ampicillin-resistant E coli and Enterobacteriaceae isolates were independent of exposure to intrapartum antibiotic prophylaxis. In other words, these null hypotheses were that the proportion of subjects with "absent" results for the entry culture and "present" results for the postpartum culture was equal to the proportion of subjects with "present" results for the entry culture and "absent" results for the postpartum culture.
Assuming an 85% rate of colonization with one or more Enterobacteriaceae at the postpartum culture and a 40% baseline rate of resistance to ampicillin, 107 patients each in the ampicillin and penicillin arms of the study were needed to detect a 50% increase in the proportion of resistant organisms in the ampicillin group as compared with the penicillin group, with a power of 0.80 and a two-tailed of 0.05. To specifically evaluate the differences between the two antibiotics, we wanted this calculated number of subjects in each arm of the per-protocol analysis. Therefore, we allowed for 10% of subjects to report a penicillin allergy and receive clindamycin, 15% of subjects to undergo cesarean delivery and receive cefazolin as prophylaxis against puerperal endometritis, 20% of subjects to deliver before administration of the second dose, and 5% of subjects to require additional antibiotic therapy for chorioamnionitis or other infections. Including these allowances, the calculated total sample size needed was approximately 370.
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RESULTS |
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Maternal demographic data for these groups are shown in Table 1
. Almost half of the women in the study had received antibiotics at some point during their antenatal courses. Table 2 contains data regarding delivery route, doses of intrapartum antibiotic prophylaxis received, and the secondary outcomes of maternal infections. Neonatal demographic data and delivery outcomes are shown in Table 3. There was only one neonatal death in the study. That infant had hypoplastic left heart syndrome and died from complications unrelated to infection. There was a single case of culture-confirmed early-onset neonatal infection in the study, and the infant’s blood culture grew Bacteroides fragilis.
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. The proportions of women with at least one strain of ampicillin-resistant E coli did not differ significantly between treatment groups at study entry or postpartum. Similarly, there was no significant difference between treatment groups for the proportions of women with one or more ampicillin-resistant Enterobacteriaceae at study entry or postpartum.
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. For this analysis, 116 women (66.3%) remained in the ampicillin group, and 110 women (62.1%) remained in the penicillin group. Similar to the intent-to-treat analysis, there were no statistically significant differences in the proportions of women with ampicillin-resistant E coli or Enterobacteriaceae between treatment groups at either the entry or postpartum cultures.
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and 5 show that exposure to intrapartum antibiotic prophylaxis was associated with significant increases in the proportions of subjects with ampicillin-resistant organisms, regardless of treatment group. All subsets in both the intent-to-treat and per-protocol analyses had significantly more subjects with ampicillin-resistant isolates in the postpartum as compared with the entry cultures, for E coli isolates specifically, or Enterobacteriaceae in general. Of 555 Enterobacteriaceae isolates, there were only 60 isolates with intermediate susceptibility to ampicillin. For purposes of analysis, these isolates were considered to be resistant to ampicillin. If these few isolates were considered to be sensitive to ampicillin, none of the differences or lack of differences between groups change (data not shown).
There were 69 women enrolled because of growth of group B streptococci in a urine culture in the current pregnancy. Six of these women were not considered in the analysis of this clinical trial because of a history of allergy to pencillin. Of the remaining women, 28 of them had colony counts of more than 100,000 colonies per mL and were treated with a course of oral penicillin. The ampicillin susceptibility results for the gram-negative organisms isolated from these subjects did not differ significantly from the rest of the study population.
Subjects whose postpartum cultures were done 8–16 hours postpartum were compared with those whose postpartum cultures were done 28–36 hours postpartum. Ampicillin susceptibility results for the gram-negative organisms isolated from these subjects did not differ between these groups or from the rest of the study population.
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DISCUSSION |
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Despite two recent reports to the contrary,18,19 there is a growing body of evidence suggesting that more widespread use of intrapartum antibiotic prophylaxis with ampicillin is associated with increased rates of early-onset neonatal infection with ampicillin-resistant gram-negative organisms12–14 (O’Reilly G, Hitti J, Brock B, Watts DH, Gill P, Benedetti T. Gram-negative sepsis among low-birth-weight infants: Infection rates before and after initiation of group B streptococcus prophylaxis [abstract 0028]. Am J Obstet Gynecol 2001;184:S14). This effect in these retrospective studies was largely confined to preterm infants. Because of this fact, we limited our study to women at 36 weeks’ gestation or longer. Because early-onset neonatal infection with any organism is a relatively uncommon event in general, and is less common in term infants, we did not expect to detect many cases of confirmed neonatal infection, and this was the case in our study. Therefore, we cannot make conclusions from our data regarding the effect of intrapartum antibiotic prophylaxis on the overall attack rate of gram-negative early-onset neonatal infection.
However, we think that postpartum lower genital tract culture is a reasonable way to evaluate which bacteria an infant is exposed to during his or her birth. The fact that we saw no significant differences in likelihood of ampicillin-resistant E coli or Enterobacteriaceae in any of the subgroups between ampicillin and penicillin treatment groups argues strongly against any real advantage of one antibiotic over the other. Furthermore, the proportions of these ampicillin-resistant organisms in the postpartum, compared with the entry, cultures were consistently increased in both treatment groups. This fact leads us to conclude that intrapartum antibiotic prophylaxis, regardless of agent used, is the key factor that increases the probability that early-onset neonatal infection with gram-negative organisms will be caused by ampicillin-resistant organisms. The studies that concluded that intrapartum antibiotic prophylaxis with ampicillin was the key factor may only have been partly correct.
The possibility that increased use of intrapartum antibiotic prophylaxis may increase the likelihood of a more lethal type of early-onset sepsis should cause the obstetric community to review this practice critically. Because of this possible adverse effect of prophylaxis, the administration of intrapartum antibiotics ideally should be limited to those women who may benefit from it. Until a vaccine against all clinically important serotypes of group B streptococci is available and obviates the need for prophylactic antibiotics, a rapid identification method that could be used at the time of labor to target colonized women would be a welcome addition to clinical practice. Ongoing surveillance of neonatal sepsis patterns will be an important factor in determining the future role of intrapartum antibiotic prophylaxis against early-onset neonatal infection with group B streptococci.
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Footnotes |
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Received December 28, 2001. Received in revised form March 22, 2002. Accepted April 11, 2002.
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REFERENCES |
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2. Boyer KM, Gadzala CA, Kelly PD, Gotoff SP. Selective intrapartum chemoprophylaxis of neonatal group B streptococcal early-onset disease. III. Interruption of mother-to-infant transmission. J Infect Dis 1983;148:810–6.[Medline]
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16. Schrag SJ, Zywicki S, Farley MM, Reingold AL, Harrison LH, Lefkowitz LB, et al. Group B streptococcal disease in the era of intrapartum antibiotic prophylaxis, 1993–1998. N Engl J Med 2000;342:15–20.
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18. Chen KT, Tuomala RE, Cohen AP, Eichenwald EC, Lieberman E. No increase in rates of early-onset neonatal sepsis by non-group B Streptococcus or ampicillin-resistant organisms. Am J Obstet Gynecol 2001;185:854–8.[Medline]
19. Baltimore RS, Huie SM, Meek JI, Schuchat A, O’Brien KL. Early-onset neonatal sepsis in the era of group B streptococcal prevention. Pediatrics 2001;108:1094–8.
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